The beneficial effect of Bacteroides Fragilis (BF839) as a supplementary treatment in drug-resistant epilepsy: a pilot study_Journal of Epilepsy

Authors：

 DENG Yuhong ^1,2,3 , LIN Chuhui ³ , CAO Dezhi ⁴

1. Institute of Neuroscience and Department of Neurology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China;
2. Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou 510260, China;
3. Department of Clinical Nutrition , the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, GuangdongProvince, 510260, China;
4. Department of Neurology, Shenzhen Children's Hospital, Shenzhen 5180038, China;

Corresponding author：

DENG Yuhong, Email: 1376708863@qq.com

Keywords：

Epilepsy; Bacteroides Fragilis; Microbiota; Autoimmune-associated epilepsy; Drug-resistant epilepsy

DOI：

10.7507/2096-0247.20210046

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Objective The purpose of this study was to find a new method for the treatment of drug-resistant epilepsy, and to study the efficacy and safety of Bacteroidesfragilis (BF839) in the adjunctive treatment of refractory epilepsy, as well as the improvement of comorbidity.Methods A prospective, single-arm, open pilot clinical study was designed for the additive treatment of drug-resistant epilepsy using BacteroidesFragilis 839 (BF839). 47 patients with refractory epilepsy, who were admitted to the epilepsy outpatient clinic of the Second Affiliated Hospital of Guangzhou Medical University from April 2019 to October 2019, were enrolled and treated with BF839 adjunct treatment. The primary efficacy endpoint was median percent reduction from baseline in monthly (28-day) seizure frequency for the 16-week treatment period. Other efficacy analysis included response rate(proportion of patients with ≥ 50% seizure reduction) in the 16 weeks period, the proportion of patients seizure free and the retention rate after12 months intervention, and the observance of the side effects and comorbidities.Results The median reduction percent of all seizure types was −53.5% (P=0.002). The response rate was 61.1% (22/36). 8.5% (4/47) patients seizure free at 12 months. The retention rate at 12 months was 57.4% (27/47). The side effects were diarrhea 4.3% (2/47) and constipation 4.3% (2/47). 48.9% (23/47) of the patients reported improvement in comorbidities, with cognitive improvement of 21.2% (10/47).Conclusion BF839 can be used as an effective additive therapy to treat drug-resistant epilepsy. It is safe and beneficial to the improvement of comorbidities. This is the first time in the world that a single intestinal strain has been reported to be effective in treating drug-resistant epilepsy. This research has important implications.

Citation： DENG Yuhong, LIN Chuhui, CAO Dezhi. The beneficial effect of Bacteroides Fragilis (BF839) as a supplementary treatment in drug-resistant epilepsy: a pilot study. Journal of Epilepsy, 2021, 7(4): 288-295. doi: 10.7507/2096-0247.20210046 Copy

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2.	Cryan JF, O'Riordan KJ, Cowan CSM, et al. The Microbiota-Gut-Brain Axis. Physiol Rev., 2019, 99(4): 1877-2013.
3.	Zhi He, Bo-Ta Cui, Ting Zhang, et al. Fecal microbiota transplantation cured epilepsy in a case with Crohn’s disease: The first report. World J Gastroenterol, 2017, 23(19): 3565-3568.
4.	Olson CA, Vuong HE, Yano JM, et al. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. Cell, 2018, 173(7): 1728-1741.
5.	张季阶, 于丽娴. 一株无毒脆弱拟杆菌的分离鉴定. 宁夏医学杂志, 1991, 13(4): 216-218.
6.	张季阶, 张洪梅, 张翼, 等. 脆弱拟杆菌(BF839)菌液的临床应用研究. 中国生物制品学杂志, 1995, 8(2): 63-65.
7.	Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 512-521.
8.	Gómez-Eguílaz M, Ramón-Trapero JL, Pérez-Martínez L, et al. The beneficial effect of probiotics as a supplementary treatment in drug-resistant epilepsy: a pilot study. Benef Microbes, 2018, 9(6): 875-881.
9.	Lim KS, Lotay N White R, et al. Efficacy and safety of retigabine/ezogabine as adjunctive therapy in adult Asian patients with drug-resistant partial-onset seizures: a randomized, placebo controlled Phase III study. Epilepsy and Behavior, 2016, 61: 224-230.
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12.	Jozwiak S, Terczynski A. Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in patients with carbamazepine- or valproate-resistant epilepsy. Seizure, 2000, 9(7): 486-92.
13.	Steinhoff BJ, Trinka E, Wieser HG, et al. Levetiracetam in patients with refractory epilepsy: results of the SKATE trial in Austria, Germany and Switzerand. Seizure, 2005, 14(7): 490-6.
14.	Halász P, Kälviäinen R, Mazurkiewicz-Beldzinska M, et al. Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial. Epilepsia, 2009, 50: 443-453.
15.	Tassinari CA, Michelucci R, Chauvel P, et al. Double-blind, placebo-controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsy. Epilepsia, 1996, 37(8): 763-8.
16.	Chung SS, Fakhoury TA, Hogan RE, et al. Once-daily USL255 as adjunctive treatment of partial-onset seizures: randomized phase III study. Epilepsia, 2014, 55(7): 1077-1087.
17.	Chen Z, Brodie MJ, Liew D, et al. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: A 30-year longitudinal cohort study. JAMA Neurol, 2018, 75: 279-286.
18.	Lee SK, Lee SA, Kim DW, et al. A randomized, open-label, multicenter comparative trial of levetiracetam and topiramate as adjunctive treatment for patients with focal epilepsy in Korea. Epilepsy Behav, 2019, Aug, 97: 67-74.
19.	Mazmanian SK, Liu CH, Tzianabos AO, et al. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell, 2005, 122(1): 107-118.
20.	Bowman LM, Holt PG. Selective Enhancement of Systemic Th1 Immunity in Immunologically Immature Rats with an Orally, Administered Bacterial Extract. Infection & Immunity, 2001, 69(6): 3719-27.
21.	Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A, 2010, 107(27): 12204-12209.
22.	Erturk-Hasdemir D, Kasper DL. Finding a needle in a haystack: Bacteroides fragilis polysaccharide A as the archetypical symbiosis factor. Ann N Y Acad Sci, 2018, 1417(1): 116-129.
23.	Brodie MJ, Zuberi SM, Scheffer IE, et al. The 2017 ILAE classification of seizure types and the epilepsies: what do people with epilepsy and their caregivers need to know? Epileptic Disord, 2018, 20(2): 77-87.
24.	Steriade C, Britton J, Dale RC, et al. Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: Conceptual definitions. Epilepsia., 2020, 61(7): 1341-1351.
25.	Britton J. Autoimmune epilepsy. Handb Clin Neurol, 2016, 133: 219-45.
26.	Husari KS, Dubey D. Autoimmune Epilepsy. Neurotherapeutics, 2019, 16(3): 685-702.
27.	Ong MS, Kohane IS, Cai T, et al. Population-Level Evidence for an Autoimmune Etiology of Epilepsy. JAMA Neurol, 2014, 71(5): 569-574.
28.	Ravizza T, Gagliardi B, NoéF, et al. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis, 2008, 29(1): 142-160.
29.	Aronica E, Crino PB. Inflammation in epilepsy: clinical observations. Epilepsia, 2011, 52(3): 26-32.
30.	Crespel A, Coubes P, Rousset MC, et al. Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res, 2002, 952(2): 159-169.

1. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia, 2010, 51(6): 1069-1077.
2. Cryan JF, O'Riordan KJ, Cowan CSM, et al. The Microbiota-Gut-Brain Axis. Physiol Rev., 2019, 99(4): 1877-2013.
3. Zhi He, Bo-Ta Cui, Ting Zhang, et al. Fecal microbiota transplantation cured epilepsy in a case with Crohn’s disease: The first report. World J Gastroenterol, 2017, 23(19): 3565-3568.
4. Olson CA, Vuong HE, Yano JM, et al. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. Cell, 2018, 173(7): 1728-1741.
5. 张季阶, 于丽娴. 一株无毒脆弱拟杆菌的分离鉴定. 宁夏医学杂志, 1991, 13(4): 216-218.
6. 张季阶, 张洪梅, 张翼, 等. 脆弱拟杆菌(BF839)菌液的临床应用研究. 中国生物制品学杂志, 1995, 8(2): 63-65.
7. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 512-521.
8. Gómez-Eguílaz M, Ramón-Trapero JL, Pérez-Martínez L, et al. The beneficial effect of probiotics as a supplementary treatment in drug-resistant epilepsy: a pilot study. Benef Microbes, 2018, 9(6): 875-881.
9. Lim KS, Lotay N White R, et al. Efficacy and safety of retigabine/ezogabine as adjunctive therapy in adult Asian patients with drug-resistant partial-onset seizures: a randomized, placebo controlled Phase III study. Epilepsy and Behavior, 2016, 61: 224-230.
10. Farkas V, Steinborn B, Flamini JR, et al. Efficacy and tolerability of adjunctive lacosamide in pediatric patients with focal seizures. Neurology, 2019, 93: e1212-e1226.
11. French JA, Baroldi P, Brittain ST, et al. Efficacy and safety of extended-release oxcarbazepine (Oxtellar XR™) as adjunctive therapy in patients with refractory partial-onset seizures: a randomized controlled trial. Acta Neurol Scand, 2014, 129(3): 143-153.
12. Jozwiak S, Terczynski A. Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in patients with carbamazepine- or valproate-resistant epilepsy. Seizure, 2000, 9(7): 486-92.
13. Steinhoff BJ, Trinka E, Wieser HG, et al. Levetiracetam in patients with refractory epilepsy: results of the SKATE trial in Austria, Germany and Switzerand. Seizure, 2005, 14(7): 490-6.
14. Halász P, Kälviäinen R, Mazurkiewicz-Beldzinska M, et al. Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial. Epilepsia, 2009, 50: 443-453.
15. Tassinari CA, Michelucci R, Chauvel P, et al. Double-blind, placebo-controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsy. Epilepsia, 1996, 37(8): 763-8.
16. Chung SS, Fakhoury TA, Hogan RE, et al. Once-daily USL255 as adjunctive treatment of partial-onset seizures: randomized phase III study. Epilepsia, 2014, 55(7): 1077-1087.
17. Chen Z, Brodie MJ, Liew D, et al. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: A 30-year longitudinal cohort study. JAMA Neurol, 2018, 75: 279-286.
18. Lee SK, Lee SA, Kim DW, et al. A randomized, open-label, multicenter comparative trial of levetiracetam and topiramate as adjunctive treatment for patients with focal epilepsy in Korea. Epilepsy Behav, 2019, Aug, 97: 67-74.
19. Mazmanian SK, Liu CH, Tzianabos AO, et al. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell, 2005, 122(1): 107-118.
20. Bowman LM, Holt PG. Selective Enhancement of Systemic Th1 Immunity in Immunologically Immature Rats with an Orally, Administered Bacterial Extract. Infection & Immunity, 2001, 69(6): 3719-27.
21. Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A, 2010, 107(27): 12204-12209.
22. Erturk-Hasdemir D, Kasper DL. Finding a needle in a haystack: Bacteroides fragilis polysaccharide A as the archetypical symbiosis factor. Ann N Y Acad Sci, 2018, 1417(1): 116-129.
23. Brodie MJ, Zuberi SM, Scheffer IE, et al. The 2017 ILAE classification of seizure types and the epilepsies: what do people with epilepsy and their caregivers need to know? Epileptic Disord, 2018, 20(2): 77-87.
24. Steriade C, Britton J, Dale RC, et al. Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: Conceptual definitions. Epilepsia., 2020, 61(7): 1341-1351.
25. Britton J. Autoimmune epilepsy. Handb Clin Neurol, 2016, 133: 219-45.
26. Husari KS, Dubey D. Autoimmune Epilepsy. Neurotherapeutics, 2019, 16(3): 685-702.
27. Ong MS, Kohane IS, Cai T, et al. Population-Level Evidence for an Autoimmune Etiology of Epilepsy. JAMA Neurol, 2014, 71(5): 569-574.
28. Ravizza T, Gagliardi B, NoéF, et al. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis, 2008, 29(1): 142-160.
29. Aronica E, Crino PB. Inflammation in epilepsy: clinical observations. Epilepsia, 2011, 52(3): 26-32.
30. Crespel A, Coubes P, Rousset MC, et al. Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res, 2002, 952(2): 159-169.

Journal of Epilepsy

The beneficial effect of Bacteroides Fragilis (BF839) as a supplementary treatment in drug-resistant epilepsy: a pilot study

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